The hepatic metabolism of spontaneously diabetic (db/db) and obese (ob/ob) mice and of mice made insulin deficient with streptozotocin will be examined using the technique of liver perfusion. Attempts will be made to define the relative roles of substrate supply and of changes within the liver in the genesis of the diabetic and obese syndromes. Studies of metabolic balances and of isotope incorporation from labeled substrates into products such as glucose, glycogen, ketone bodies, lipoproteins, urea and CO2 will be employed to identify changes in metabolic pathways. Tissue metabolite analyses and enzyme assays will be used to further define key reactions involved in metabolic control. Correlations between postulated enzyme changes and alterations in metabolism will be tested for. The possible roles of free and bound cyclic AMP and of cyclic AMP-dependent protein kinase(s) in the genesis of the diabetic or obese syndromes will be examined.